Chemical compounds and process of preparing the same



I Patented Dec. 21, 1949 2,492,194

UNITED STATES PATENT OFFICE CHEMICAL COMPOUNDS AND PROCESS OF PREPARING THE SAME Lewis B. Sarett, Princeton, N. J., asslgnor to Merck & 00., Inc., Eahway, N. J., a corporation of New Jersey No Drawing. Original application July 14, 1945,

Serial No. 605,194. Divided and this application February 23, 1946, Serial No. 649,766

4 Claims. (Cl. 260397.4) l 2 This invention is concerned generally with by writing the -17 substituent (hydroxyl) to novel chemical compounds of the cyclopentanodithe right of the 0-17 carbon side chain, thus methylpolyhydrophenanthrene series and to .processes of preparing same; more particularly it relates to novel compounds useful as inter- H015! mediates in the synthesis of the adrenal cortical hormone A4,5-3,11,20-triketo-1'7 (p) 2l-dihydroxy' pregnene. This application is a divisional of copending application Serial No. 605,194 filed July 14, 1945' now abandoned. in the latter case above the side chain, thus This hormone is known to occur naturally in on the adrenal cortex; it has the structural formula: X

21CH|OH H m s. The stereochemical relationship of rings A 0 and B is indicated in the formulae by a solid line f representing the valence bond in the cis con- I c 1 figuration. gi l g H, In accordance with the present invention it is 1& l 9 now found this hormone can be synthesized by i A 1 B SCH reactions indicated asfollows: {a} \6/ a CH; CH;

H H, 11-0 on! (Standard numbering of O-positions.) CHI o 0 This formula, for purposes of convenience, is acylmng hereinafter reproduced below in the abbreviated CHI w form:

CHiOH =o 110 R0 OH: OH 85 I I n 0 acyl-halidcon la a 0 CH] CH 0 g tin-com H-COX OH on,

In the following description of the invention, the stereochemicai relationships of substituents CH MN! CH are indicated by the following conventions:

1. A substituent at the 0-3 position which is trans to the 0-10 methyl group is parenthetically designated (a). R0 R0 2. A substituent at the C-17 position, the stereochemical configuration of which is identical with H E that of the naturally occurring adrenal hormones, Iv In is parenthetically designated (3) the epimeric configuration is designated (a). In the structural formulae the former configuration is shown H OH CHI, CH=CHg halogenaflng agent CiH-C 33X CH-CHaO H" M O R" CH XVII hydrolysis CH-CHaOR' CHCH:OH

loxidation GH-CHaO 8'" 08-08101! OH: OH h d l 0\ on it? H XXI xx 0 m afl haunt H CHIOH 41H 0H (FR-0808"" OH: OH OH 11 dm sting o\ 11 OH 3- OH xxn XXIII l acylating agent RI!!! 0 BIIII' H 0 E!!! H 0 all!!! CH )0H CB: 08 O 0 CH X" CH XXV XXIV cmo R C330 R H0 RIIIII RIIIII OH; OH OH: /OH 0 A OH; pyridine CH:

XXVI x!) XXV I hydrolysis CHO R CHOH H OH H-OH OH: OH CH: CH

(R920 CH:

XXVII cmom on. on on on 10 OH: I

Km xxx :0 l ydmiy l a La Om OH O OH: I

In the above formulae, R, R, R", R', R"", R"", and Rare acyl; x, X and X" are halogen; and M is an alkali metal or an alkaline earth metal /2.

The reactions above indicated are conducted as follows:

3-hydroxy-ll-keto-bisnorcholanic acid (I) is acylated producing 3-acyloxy-11-keto-bisnorcholanic acid (11) which is treated with an agent capable oi converting an organic carboxylic acid to the corresponding acid halide, thus forming the acid halide of 3-acyloxy-1i-keto-bisnorcholanic acid (111). Upon treatment of this acid halide with an alkali metal azide or alkaline earth metal azide, the azide of 3-acyloxy-11-keto-bisnorcholanic acid (IV) is formed. Decomposition of this azide with an acidic aqueous solution produces 3-acy1oXy-1l-keto-20-aminopregnane (v).

A'= -3-acyloxy-1l keto-pregnene (VII) and a minor amount of 3-acy1o -1l-keto-20-hydroxypreznane (VIII) results. The proportion of the to desired compound (VI) present in this mixture can be increased by treating the mixture with an aromatic sulfonyl halide followed by further ed with ozone followed by decomposition or the ozonide, producing 3-acyloxy-l1,l7-diketoeti0- cholane (IX) and 3-acyloxy-11-keto-17-formyletiocholane (X) Compound (X) is oxidized to 3- acyloxy-ll-ketoetiocholanic acid (XI) which is separated from compound (11!) by extraction with alkali.

Compound (no is hydrolyzed to form 3-hy- 76 droxy-ihl'l-diketoetiocholane (III) which is treated with acetylene to form 3,17-dihydroxyli-keto-pregnlne-ZO (Inn). This compound (XIII) is catalytically hydrogenated to produce A'-'' -3,17-dihydroxy 11 ketopregnene (XIV) which is acylated to form A -ii-acyloxy-flhydroxy-ll-ketopregnene (XV), and this compound is halogenated to produce A -3-acyloxyll-keto-Zl-halopregnene (XVI). When treated with an alkali metal salt or alkaline earth metal salt of an organic acid, this compound yields -3,21-diacyloxy l1 ketopregnene (XVII) which is hydrolyzed producing A -3,21-dihydroiw-ll-ketopregnene (XVIII). The latter product (XVIII) is partially esterifled and the mono ester (XIX) thus produced is oxidized to convert the unesterified hydroxy group in the 3 position to a keto group, thereby yielding the ester of A"-=3,11-diketo-2l-acyloxy-pregnene (XX). This product (XX) is hydrolyzed and the A -3,11 diketo 21 hydroxypregnene (XXI) thus formed is acylated producing A -3,11- diketo-Zl-acyioxypregnene (XXII). Hydroxylation at the unsaturation of the last mentioned compound (XXII) results in the production of 3,11 diketo 17(p) 30,21 trihydroxypregnene ()QCHI) which is then acylated to form 3,11- diketo-1'I( p) -hydroxy 20,21 diacyloxypregnene (XXIV). When brominated, this compound yields 3,11-diketo-4-bromo- 17 (p) -hydroxy-20,21- diacyloxypregnene (XXV) This compound is then treated with a reagent capable of removing the'elements of hydrogen bromide, thereby producing A -'*-3,11-diketo 17 (s) -hydroxy-20,2l-diacyloxypregnene which on hydrolysis forms A --3,11-diketo-17(p) 20,21 -trihydroxypregnene Partial acylation of this compound (XXVII) gives A 3,11-diketo-1'Hp) ,20 dihydroxy-21-acyloxypregnene (XXVHI) which, when oxidized. yields a mixture of A -3,1l,20-triketo-17(B) -hydroxy-21- acy1oxypregnene( XXIX) and A -3,1l,17-triketo androstene (XXX). Compounds (XXIX) and (XXX) may be separated by conventional operations, for example chromatography, and compound (XXIX) hydrolyzed to produce the desired adrenal hormone, A -3,l1-20-triketo- 1'1 3) ,21-dihydroxypregnene.

This invention is concerned with compounds of the type represented by the intermediates 23 and 24 above and also with processes of producing same: These intermediates are represented by the formula:

CHaOR HOR- CH; OH

in which R is acyl or hydrogen.

The starting material employed in the process according to this invention, A -3,11-diketo-21- acyloxypregnene, may be obtained as described in copending application Serial No. 649,765 filed February 23, 1946.

In accordance with this invention A -3,11- diketo-2-acyioxypregnene is treated with osmium tetroxide in an inert solvent and the osmate so formed is hydrolyzed to give 3,i1-diketo-17,20,2i-

trihydroxypregnane having the structural for mula:

irnon m HOB CH: OH

Mild acylation of the latter, preferably using an acid anhydride, gives the desired 3,11-diketo-17 (B) hydroxy-20,2l-diacyloxypregnane, having 25 the structural formula:

CHaOB tmoa so on on R being acyl. Instead of an acid anhydriue, a

carboxylic acid alone or in conjunction with its corresponding anhydride may be used to effect the acylation. Acylating agents capable of introducing the acyl group of propionic, butyric, valeric, caproic or capric acid, preferably from a lower aliphatic acid, 1. e. one having 6 carbon atoms or less, may be used satisfactorily.

In the following example, the conversion of the A -3,1l-diketo-Zl-acyloxypregnene to 3.11- diketo-l'l (p) -hydroxy-20,21 diacyioxypregnane is described, but it will be understood this example is for purpose of illustration and that the invention is not limited thereto.

Example A solution of 900 mg. of A "'=-3,11-diketo-21- acyloxypregnane in 14 cc. of absolute ether was treated with 7'10 mg. of osmium tetroxide and 450 mg. of anhydrous pyridine. The mixture was permitted to stand at room temperature overnight, the ether was then removed in vacuo, and the residue dissolved in 35 cc. of alcohol and treated with a solution of 5.5 grams of sodium sulfite in 24 cc. of water. The mixture was refluxed 3 /2 hours, filtered, and the filtrate concentrated in vacuo to a small volume and extracted with chloroform. The chloroform solution was washed with water and concentrated to dryness in vacuo.

giving 3,11 diketo 17 (18) ,20,21-trihydroxypregnane, which was obtained in about yield as the crystalline hydrate (melting point, approxi- 75 mate1y C.)

The 20,21-diacetate was prepared by dissolving the above-described diketo trihydroxy compound in a mixture of cc. of pyridine and 5 cc. of acetic anhydride, permitting the solution to stand at room temperature for 40 hours, and crystallizing the product from ether and from a small volume of ethyl acetate. The 3,11-diketo-17 S) hydroxy-20,2l-diacetoxypregnane diacetate so obtained in about 100% yield had a melting point of 213-214 C. [a] |-93.

The temperatures mentioned in the example are room temperatures unless otherwise indicated. The temperatures, however, are not critical and the reactions may be carried out at highat or lower temperatures; but extremely high temperatures should be avoided because of the likelihood of decomposition of the desired products which may result from operation at such temperatures.

Unless otherwise stated, the reagents can be used in different proportions than are indicated in the above example as the proportions unless otherwise indicated are not critical, although enough of the reagents should be employed to insure substantially complete reaction to produce the desired products.

The specific rotation for 3,11-diketo-20,2l-diacetylpregnane-l'? (5) -hydroxypregnane, indicated above by the symbol lul was determined in acetone solution using the D line of sodium.

Various changes and modifications might be made in my invention as defined herein without departing from the scope thereof. It is my intention that these changes and modifications, to the extent that they are comprehended within the scope of the appended claims, shall be considered as part of my invention.

What is claimed is:

1. 3,11-diketo 17 (p) 20,21 trihydroxypregnane.

2. 3,11-diketo-17 (p)-hydroxy-20.21-diacetoxypregnant:

3. The process that comprises reacting a compound of the cyclopentanoperhydrophenanthrene series having the basic structural formula:

CHIOR CHI H CHI with osmium .0 Number 10 drolyzing the reaction product to obtain a compound having the basic structural formula:

CHaOH HOH OH: OH

and treating this compound with a lower aliphatic acylating agent to produce the corresponding 20,21-diacyloxy compound.

4. The process that comprises reacting a compound of the cyclopentanoperhydrophenanthrene wherein R is a member of the class consisting of lower aliphatic acyl and hydrogen, with osmium tetroxide in the presence of a tertiary amine, hy-

' drolyzing the reaction product to obtain a compound having the basic structural formula:

CHIOH non era on n and treating this compound with acetic anhydride to produce the corresponding 20,21-diacyloxy compound.

LEWIS H. SARETI.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Name Date 2,265,143 Butenandt Dec. 9, 1941 

